Cyanohydrination of an aromatic aldehyde

ABSTRACT

A cyanohydrination catalyst for the preparation of alphahydroxynitriles from aldehydes and ketones comprises a solid cyclo(D-phenylalanyl-D-histidine) dipeptide having a non-crystalline or amorphous component.

This is a division of application Ser. No. 535,500, filed Sept. 26,1983, U.S. Pat. No. 4,554,102.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a cyanohydrination cyclic dipeptidecatalyst, and a method of directly preparing or activating thecatalysts.

2. Description of the Prior Art

Asymmetric synthesis of R-mandelonitrile by addition of hydrogen cyanideto benzaldehyde in the presence of a synthetic dipeptide catalyst isknown in the art, as in Oku, Jun-ichi and Shohei Inoue, J.C.S. Chem.Comm., pages 229-230 (1981), and other Oku publications wherecyclo(L-phenylalanyl-L-histidine) containing 1/2 mole of water ofcrystallization was used. However, it has been found thatcyclo(L-phenylalanyl-L-histidine and cyclo(D-phenylalanyl-D-histidine)are not necessarily as satisfactory a catalyst for the preparation ofcertain S-α-cyano-alcohols of larger chemical structure, particularly(S)- or (R)-α-cyano-3-phenoxybenzyl alcohol and ring-substitutedderivatives thereof. After encountering difficulty in obtaining highenantiomeric excesses, it was discovered that the high enantiomericexcess in the reaction to prepare (S)- or (R)-α-cyano-3-phenoxybenzylalcohols was dependent on a particular physical form of thecyclo(L-phenylalanyl-L-histidine) and cyclo(D-phenylalanyl-D-histidine).

SUMMARY OF THE INVENTION

The present invention is directed to a catalyst for cyanohydrination ofaldehydes or ketones, comprising a solidcyclo(D-phenylalanyl-D-histidine) having a substantially non-crystallinecomponent. In other words, the catalyst has a component having asubstantially amorphous or non-crystalline structure.

While the precise form of thiscyclo(D-phenylalanyl-D-histidine)dipeptide is not known, it appears thatin the activated (amorphous or non-crystalline) form, a number of theavailable --NH groups in the dipeptide are free of intermolecularhydrogen bonding to the available --C═O groups of the dipeptide crystallattice as compared to the less active (crystalline component) form.This is believed to involve the formation of a less bonded linear orplanar (or sheet) form of peptide structure as opposed to the highlybonded ribbon (or chain) form of peptide structure because of theincrease in the number of --NH groups free of intermolecular hydrogenbonding to available --C═O groups in the dipeptide lattice. Such beingthe case, the degree of amorphousness or non-crystallinity is mostreadily determined by X-ray diffraction.

The wide-angle X-ray scattering (WAXS) measurements were carried out inreflection by means of a Philips APD3600/02 automated X-raydiffractometer. The samples were scanned at 20° C. in air from 5.0° to60.0° 2θ at 0.02 degree increments, and 0.6 second time increments withCu Kα radiation (40 KV, 35 ma).

The percent crystallinity was determined by a modified Hermans andWeidinger method (P. H. Hermans and A. Weidinger, Makromol. Chem., 50,98 (1961)). The diffuse background scattering below the main peaks wasconstructed assuming a linear baseline between 5°≦2θ≦60° andapproximating the amorphous scattering with a smooth curve. The X-raycrystallinity, W_(c), was calculated from the integrated crystalline andamorphous intensities F_(c) and F_(a) by the equation W_(c) =F_(c)/(F_(c) +F_(a)). The various definitions can be found in the text H. P.Klug and L. E. Alexander, X-Ray Diffraction Procedures forPolycrystalline and Amorphous Materials, Wiley-Interscience, New York,(1974).

As used herein the terms "amorphous" or "non-crystalline" define activecatalyst materials which have an amorphous or non-crystalline componentas determined by the area of the X-ray diffraction spectra obtained bythe method described above. Preferably, the "amorphous" or"non-crystalline" component of the materials as defined by the X-raydiffraction spectra is about 45% to about 65% or higher. Preferably, the"amorphous" or "non-crystalline" component is about 65% or higher.

The catalysts are also analyzable by photomicrographs in whichinefficient catalysts consist of agglomerates of fine crystallites.Crystallites are not evident in photomicrographs of active catalysts,which when, for example, are spray-dried, take the form ofhollow-appearing spheres.

Alternative methods are available to define the terms amorphous andnon-crystalline by infrared or nuclear magnetic resonance spectralstudies or by swelling of the material, e.g. in contact with thereactants of the cyanohydrination process.

In a preferred method the dipeptide is prepared by the route describedbelow in which HIS means histidine and PHE means phenylalanine. ##STR1##

The cyclo(D-phenylalanyl-D-histidine)dipeptide catalyst can also beprepared by other conventional peptide syntheses, for example, as inGreenstein, J. P. and M. Winitz, "Chemistry of the Amino Acids", JohnWiley & Sons, Inc., New York, 1961.

When the catalyst is prepared by conventional methods in the presence ofwater, and as a solid, it can also contain solvent (e.g. water) ofcrystallization. The optically-active, cyclo(D-phenylalanyl-D-histidine)catalyst of the invention thus includes the presence or absence ofsolvent (e.g. water) of crystallization.

The solid catalyst can be recovered by extraction with acid followed byneutralization with a base or preferably by treating with (dissolvingin) a solvent, for example a hydroxylic solvent, including loweralkanols of 1 to 10 carbon atoms such as isopropanol or preferablymethanol (preferably with heating, e.g. to reflux or quick flash), andreprecipitating (preferably below ambient temperature) which produces aless crystalline (or more amorphous) catalyst structure.

While it is preferred to directly prepare the catalyst of the presentinvention having the non-crystalline component, it is also within thescope of this invention to prepare a substantially crystalline catalystand to subsequently activate the catalyst by converting at least part ofthe crystalline material to an amorphous form. Thus, the presentinvention is directed to both a method of directly preparing an activecyclo(D-phenylalanyl-D-histidine)dipeptide catalyst and to a method ofactivating a crystalline catalyst of this type, which methods bothinvolve reducing or preventing the formation of a substantiallycrystalline form thereof. In the case of activation of a crystallinecatalyst, the crystalline form is first broken down and then preventedat least in part from reforming.

It is believed that the breakdown of or the prevention of the formationof a number of intermolecular bonds between the amino N--H and thecarboxyl C═O groups in the crystal lattice makes the catalyst have anamorphous or non-crystalline form. In any event, an ordered depositionof crystals of the catalyst is discouraged or reduced.

Any means which will accomplish this reduction or prevention eitherduring the catalyst preparation or an after treatment are within thescope of the invention. Among the illustrative examples of methods whichreduce or prevent the formation of a highly crystalline form of highlyordered arrangement are (a) very rapid evaporation of a solution of thecatalyst, in the presence or absence of impurities or crystallinityinhibitors; (b) rapid precipitation of the catalyst from solution bydilution in a poor solvent; (c) freeze drying of a solution of thecatalyst; (d) rapid cooling of the melted catalyst in the presence orabsence of impurities or crystallinity inhibitors; (e) use ofcrystallinity inhibitors during solidification; and the like.

The unactivated dipeptide catalyst, when recovered at the end of aconventional synthesis process, is often almost completely inactive inthe cyanohydrination reaction, apparently because it has become highlycrystalline as can be determined by X-ray diffraction. Activation, asused herein, appears to involve converting at least part of the normallycrystalline material into an amorphous form such that the dipeptide isswelled by the reaction mixture and the chiral base function of thecatalyst is made accessible to the reactants. In order to produce highchirality in the cyanohydrination product, it appears that the catalystshould preferably be essentially insoluble in the cyanohydrinationsolvent.

The first step in converting what is or what normally would be acrystalline material to an amorphous form is to break down (or prevent)formation of the intermolecular bonds in the crystal lattice. Thebreakdown readily occurs when the material is melted or dissolved in asolvent. Once this has been accomplished, a method is used that willallow the separation of the dissolved material from the solvent at arate such that normal crystallization cannot occur. There are a numberof ways in which this might be effected: (a) rapid evaporation of thesolvent, e.g. as in spray dryer; (b) rapid precipitation of the materialby pouring a solution of it into a large volume of a different solventthat is miscible with the original solvent but does not dissolve, to alarge extent, the material to be precipitated; (c) rapid freezing of asolution followed by sublimation of the solvent (freeze drying); (d)rapid cooling of the melted catalyst; and (e) use of inhibitors alone orwith any of the above methods (a)-(d). Preferably, the method used is(a) rapid evaporation of the solvent and, especially, by means of spraydrying.

Because of the polar nature and high melting point (˜250° C.) ofcyclo(D-phenylalanyl-D-histidine), the choice of solvents that willdissolve it to any appreciable extent is very limited. Potentialsolvents suitable and unsuitable that have been tested are listed inTable 1 in order of decreasing effectiveness, and the use of these willbe discussed below in relation to the method of catalyst activation viarecovery techniques or specific subsequent activation treatment.

                  TABLE 1                                                         ______________________________________                                        SOLVENTS TESTED FOR SOLUBILITY OF                                             CYCLO(D-PHENYLALANYL-D-HISTIDINE)                                                         B.P./                                                             Solvent     °C.                                                                             Solvency                                                 ______________________________________                                        Dimethyl Sulfoxide                                                                        189      Good (5-10% w)                                           Acetic Acid 118      Good                                                     Formamide   210      ≧2.3% at 25° C.                            1-Methyl-2-pyrroli-                                                                       202      ≧2.2% at 25° C.                            dinone                                                                        Dimethylformamide                                                                         153      Fair to Good, <5% at 90° C.                       Liquid Ammonia                                                                            -33      ˜2% at -40° C.                              N--methylformamide                                                                        185      ≧2.4% at 25° C.                            Acetonitrile                                                                               80      Fair to Poor, <<5% at 70° C.                      Methanol     64      1% w Hot, 0.3% w at 25° C.                        Water       100      Fair to Poor, 0.1% at 25° C.                      Acetone      55      Fair to Poor, <<1% at 25° C.                      Liquid Carbon Dioxide                                                                      78      Poor, <0.2% at 25° C.                             Carbon Disulfide                                                                           45      Very Poor                                                Diethyl Ether                                                                              35      Very Poor                                                Hydrocarbons                                                                              Var      Very Poor                                                ______________________________________                                    

The use of crystallization inhibitors is an alternative method ofreducing or preventing the crystalline form of the dipeptide. Manychemicals can be used. It is useful if the crystallization inhibitor hasa similar kind of structure or has one or more substituents similar inkind to those found in the dipeptide, but the inhibitor is not identicalto the units of the dipeptide. In the case of this dipeptide, usefulkinds of crystallization inhibitors include those materials containing a--N--H and/or --C═O group, including ureas, aldehydes and amines. Evenby-product impurities of the dipeptide process containing suchsubstituents are useful crystallization inhibitors, e.g. making animpure product can make a more active catalyst.

The present invention is usefully applied to the improvement ofcyanohydrination to obtain high enantiomeric selectivity, that is to aprocess for the preparation of optically-active alpha-hydroxynitriles ora mixture enriched therein which comprises treating the correspondingaldehyde or ketone with a source of hydrogen cyanide in a substantiallywater-immiscible, aprotic solvent and in the presence of a solid,cyclo(D-phenylalanyl-D-histidine)dipeptide having a substantiallyamorphous or non-crystalline form, as a catalyst. A use ofcyclo(D-phenylalanyl-D-histidine dipeptide catalysts is described inco-pending U.S. patent application Ser. No. 443,763, filed Nov. 22,1982, incorporated herein by reference.

A substantially water-immiscible, aprotic solvent for use in theimproved cyanohydrination process of this invention is defined as anaprotic solvent in which the solubility in water is not more than 5%v atthe reaction temperature (and does not interfere with the reaction). Forexample, the solvent is a hydrocarbon or ether solvent includingacyclic, alicyclic or aromatic materials within the above definition.For example, suitable solvents are alkanes containing from 5 to 10carbon atoms such as n-pentane, n-hexane, n-heptane, n-octane, n-nonane,n-decane and their isomers. Petroleum fractions rich in alkanes are alsosuitable, for example, gasoline with a boiling range at atmosphericpressure of between 40° C. and 65° C., between 60° C. and 80° C. orbetween 80° C. and 110° C. Petroleum ether is also suitable. Cyclohexaneand methylcyclohexanes are examples of useful cycloalkanes containingfrom 6 to 8 carbon atoms. Aromatic hydrocarbon solvents can contain from6 to 10 carbon atoms, for example, benzene, toluene, o-, m- andp-xylene, the trimethylbenzenes, p-ethyltoluene and the like. Usefulethers include diethyl ether, diisopropyl ether, methyl tert-butyl etherand the like. Preferably, the solvent is one having a boiling point ofless than about 150° C. Preferably, the solvent is toluene, diethylether or diisopropyl ether or mixtures of toluene and one of the ethers,e.g. 25/75% of diethyl ether/toluene. Toluene gives especially highenantiomeric excess when the substrate is 3-phenoxybenzaldehyde.

Preferably, the optically-active alpha-hydroxynitrile products have the(S)-configuration, absolute or relative, when derived from aldehydesand, therefore, include (S)-alpha-hydroxynitriles of the formula II##STR2## wherein m is 0 or 1; Y is 0, CH₂, C(O), A, D and E eachindependently is a hydrogen atom, a halogen atom having an atomic numberof from 9 to 35, inclusive, or an alkyl or alkoxy group containing 1 to6 carbon atoms, each optionally substituted by one or more halogen atomshaving an atomic number of from 9 to 35, inclusive. Preferably, Y is 0and m is 1. Preferably, A, D or E each independently is a hydrogen atom,a fluorine atom, a chlorine atom, a methyl group, a trifluoromethylgroup or a methoxy group. Preferably, one of D and E each is a hydrogenatom. An especially preferred embodiment of the(S)-alpha-hydroxynitriles are those of the formula above in which D is ahydrogen atom and A and E each independently is a fluorine atom or ahydrogen atom, and, preferably, when either A or E is fluorine, each islocated at the 4-position of the ring relative to the benzyl carbon whenA or relative to the Y═O bearing carbon atom when E. Especially suitablealcohols are when A is a fluorine atom at the 4-position and E is ahydrogen atom.

Non-limiting examples of alpha-hydroxynitriles of the above formula Iinclude

(S)-alpha-cyano-3-phenoxybenzyl alcohol

(S)-alpha-cyano-4-fluoro-3-phenoxybenzyl alcohol

(S)-alpha-cyano-3-(4-fluorophenoxy)benzyl alcohol

and the like.

Preferably, an aromatic aldehyde is used of the formula IV ##STR3##wherein each A is independently a hydrogen atom, a halogen atom havingan atomic number of from 9 to 35, inclusive, or an alkyl, alkenyl oralkoxy group containing 1 to 6 carbon atoms, each optionally substitutedby one or more halogen atoms having an atomic number of from 9 to 35,inclusive; B is a hydrogen atom, a halogen atom having an atomic numberof from 9 to 35, inclusive, or an alkyl, alkenyl or alkoxy groupcontaining 1 to 6 carbon atoms, each optionally substituted by one ormore halogen atoms having an atomic number of from 9 to 35, inclusive;or is group ##STR4## in which Y is 0; CH₂, C(O); m is 0 or 1 and D and Eeach independently is a hydrogen atom, a halogen atom having an atomicnumber of from 9 to 35, inclusive, or an alkyl, alkenyl or alkoxy groupcontaining 1 to 6 carbon atoms, each optionally substituted by one ormore halogen atoms having an atomic number of from 9 to 35, inclusive.

Preferably, an aldehyde is used corresponding to thealpha-hydroxynitrile previously defined and, thus, has the formula V##STR5## wherein m, A, D, E and Y have the same meanings as given in theformula above.

The source of cyanide ions is hydrogen cyanide or an agent whichgenerates hydrogen cyanide such as an alpha-hydroxynitrile such asacetone cyanohydrin, under the reaction condition. Hydrogen cyanideitself is preferred. The molar ratio of hydrogen cyanide to aldehyde orketone is from about 1.0 to about 3.0 moles per mole of aldehyde orketone and, preferably, from about 1.1 to about 2.0.

The amount of catalyst can vary. For example, it can be used in therange of from about 0.1 to about 5 mole percent based upon the weight ofthe aldehyde or ketone present, preferably about 1.0 to about 2.5 molepercent. The catalyst is preferably well dispersed in the reactionmixture.

The cyanohydrination reaction is preferably conducted by adding thealdehyde or ketone and/or solvent to the catalyst, dispersing(mechanical grinding or agitating the mixture, e.g. by stirring), addinghydrogen cyanide with or after the solvent or carbonyl compound andmaintaining the reaction conditions for an amount of time to effect theformation of the optically-active alpha-hydroxynitrile. A suitableproduct is also made when hydrogen cyanide is added first to thecatalyst, provided that the solvent and aldehyde or ketone are addedimmediately thereafter. The forming and maintaining of a well dispersedbut not necessarily homogeneous-like reaction mixture are useful.Separation and recovery of the optically-active ester product areachieved by conventional techniques, including extraction and the like.

The temperature of the cyanohydrination reaction as well as the pressurecan vary. At normal pressures, the temperature is from about -30° C. toabout 80° C., more or less. Preferably, ambient temperatures of about 5°C. to about 35° C. are convenient to give good yield, rate of reactionand enantiomeric excess of the desired optically-active product, with alower temperature of about 5° C. giving a very good selectivity.

The alpha-hydroxynitriles and their corresponding aldehydes and ketonesare generally known in the literature. The (S)-cyanobenzyl alcohols areof interest per se of as intermediates to esters, e.g. of the pyrethroidtype. For example, (S)-alpha-cyano-3-phenoxybenzyl alcohol in U.S. Pat.No. 4,273,727 or those described in commonly assigned U.S. patentapplication Ser. No. 443,513, filed Nov. 22, 1982. The (R)-cyanobenzylalcohols are also pyrethroid intermediates and the resulting esters canbe epimerized to the racemic or (S)-cyano alcohol esters by proceduresof U.S. Pat. Nos. 4,133,826 and 4,151,195.

ILLUSTRATIVE EMBODIMENTS

The following embodiments are provided for the purpose of illustratingthe invention and should not be regarded as limiting it in any way.

EMBODIMENT 1

A Niro Atomizer laboratory spray dryer with a ca 31 inch diameterchamber was assembled. In operation, 40 SCFM N₂ is heated to 140° C. andfed to the dryer chamber. A warm solution of 0.5-1.0%wcyclo(D-phenylalanyl-D-histidine) in methanol is fed via a rotary vanedatomizer to the chamber above the N₂ inlet. The droplets ofcyclo(D-phenylalanyl-D-histidine) solution are rapidly dried to givehollow spherical particles of 1 to 10 μm diameter. The combined streamis fed to a cyclone where 50-70% of the particles are captured.

Six test runs were made using 5 to 10 gm ofcyclo(D-phenylalanyl-D-histidine) each. Starting with a catalyst thatwas inefficient for cyanohydrination, all the products were activated togive good reaction rate and produce (S)-alpha-cyano-3-phenoxybenzylalcohol with EE's between 75-80% at 97% conversion of3-phenoxybenzaldehyde. Water and sodium chloride, simulating recycleoperation, apparently had no effect on activation. On the other hand,the addition of urea to further disrupt crystallization ofcyclo(D-phenylalanyl-D-histidine) did not result in any furtherimprovement. The results of the six test runs are tabulated in Table 2.

                                      TABLE 2                                     __________________________________________________________________________    ACTIVATION OF CYCLO(D-PHENYLALANYL-D-HISTIDINE) FOR SPRAY                     __________________________________________________________________________    DRYING                                                                        Catalyst   Feed Composition (Rest MeOH)                                                                     Feed                                                                              N.sub.2                                                                            Temp                                         Purity                                                                             DDCAT.sup.(d)                                                                       H.sub.2 O                                                                         NaCl                                                                              Others                                                                             Rate                                                                              Rate In                                     Experiment                                                                          % w  % w   % w % w % w  ml/min                                                                            SCFM.sup.(f)                                                                       °C.                             __________________________________________________________________________    1     87 .sup.                                                                           0.49               115 42   135                                    2     87 .sup.                                                                           0.48               225 42   ˜160                             3     92.sup.(b)                                                                         0.84               125 43   135-140                                4     92.sup.(b)                                                                         0.63  4.5          110 43   139                                    5     92.sup.(b)                                                                         0.62  4.5 1.0      135 43   137-140                                6     92.sup.(b)                                                                         0.65  --  --  0.033                                                                              125 43   139                                    7     92.sup.(b)                                                                         0.80  --  --  --   135 42   135-140                                __________________________________________________________________________                             Cyanohydrination In Toluene at 25° C.              Temp                                                                              Atomizer                                                                           Catalyst                                                                            Particle POAL.sup.(e)                                                                        (S)--POAL:CN.sup.(e)                       Experi-                                                                            Out RPM ×                                                                        Recovery                                                                            Size Time                                                                              Conversion                                                                          Selectivity.sup.(c)                        ment °C.                                                                        10.sup.-3                                                                          %     μm                                                                              hr  %     %                                          __________________________________________________________________________    1    60-75                                                                             37   46    1-12 1   92.2  91                                                                  2   95.9  90                                                                  4   96.9  90                                                                  5.5 95.9  90                                         2    60-70                                                                             31   58    1-12 1   91.3  90                                                                  3   95.5  88                                                                  4   96.7  88                                                                  5.1 98.4                                             3    55-65                                                                             37     66.sup.(a)                                                                        1-10 1   93    90                                                                  2   96.7  90                                                                  3   96.6  92                                                                  4   97.6  90                                         4    65-75                                                                             36     56.sup.(a)                                                                        1-10 1   94.6                                                                      2   96.9  90                                                                  3   98.7  89                                         5    55-65                                                                             36   68    1-10 1   93.6  91                                                                  2   96.6  90                                                                  3   95.4  91                                                                  4   97.5  90                                                                  5         90                                         6    70-75                                                                             36   58    1-10 1   92.3  90                                                                  2   91.0  90                                                                  4   94.7  89                                                                  5   96.0  90                                         7    55-70                                                                             38   77    1-10 1   93.3  93                                                                  2   96.1  91                                                                  3   95.9  92                                                                  4   97.6  92                                                                  5   96.0  91                                         __________________________________________________________________________     .sup.(a) Mostly held in cyclone by static electricity.                        .sup.(b) 96% purity by pot. titration.                                        .sup.(c) EE = 2 (selectivity)  100, %.                                        .sup.(d) DDCAT = cyclo(Dphenylalanyl-D-histidine)-                            .sup.(e) POAL = 3phenoxybenzaldehyde, (S)--POAL.CN =                          (S)--cyano-3-phenoxybenzyl alcohol.                                           .sup.(f) SCFM = standard cubic feet per minute.                          

EMBODIMENT 2

Table 3 summarizes the results of tests and scale-up experiments toactivate the cyclo(D-phenylalanyl-D-histidine) catalyst by solventevaporation, most of which were from methanol. Whereas the catalystrecovered by conventional crystallization was not very active, rapidevaporation of methanolic solutions was rather effective in producingactive catalysts (Experiments 1-11). The addition of small amounts ofimpurities (5-10% basis catalyst) appeared to help prevent normalcrystallization (compare Experiment 1, having no impurity, to thosefollowing it in the table). Except for dimethyl sulfoxide, all of theadditives gave better results than the base case. These experimentsinvolved rapid stripping of 25 ml of methanol from 0.2 g of catalyst ina rotating evaporator. Attempts to scale up Experiment 9 were onlypartially successful. The product from the first experiment had anactivity/anantiomeric excess of 88%/75%, as compared to 98%/88% in thesmaller experiment. The second of the large experiments was even lessactive, 75%/47%. Longer times required to strip off large volumes ofsolvent resulted in greater amounts of crystallization of the dipeptide,thus resulting in a less active material. A solution to this problem isto spray dry the solution so that the solids are recovered rapidly.Solvents that may be useful in this approach are methanol, liquidammonia, and acetic acid.

                                      TABLE 3                                     __________________________________________________________________________    ACTIVATION OF CYCLO(D-PHENYLALANYL-D-HISTIDINE)                               BY SOLVENT EVAPORATION                                                                                    Cyanohydrination.sup.(a)                                                  Temp                                                                              Conversion                                                                          Enantiomeric                                Experiment                                                                          Method of Evaporation                                                                           °C.                                                                        %/3 Hr                                                                              Excess, %                                   __________________________________________________________________________    1     Rapid small.sup.(b) evap. from meth-                                                            ˜0                                                                          83    79                                                anol                                                                    2     Rapid small evap. from methanol,                                                                ˜0                                                                           --96  --87                                             +5% urea                                                                3     Rapid small evap. from methanol,                                                                0-20                                                                               --95  --85                                             +10% 3-phenoxybenzaldehyde                                              4     Rapid small evap. from methanol,                                                                0-20                                                                               --99  --85                                             +10% M acetic acid                                                      5     Rapid small evap. from methanol,                                                                0-20                                                                               --99  --86                                             +10% CH.sub.3 CN                                                        6     Rapid small evap. from methanol,                                                                0-20                                                                               --97  --87                                             +10% α-isopropyl-p-chlorophenyl-                                        acetonitrile                                                            7     Rapid small evap. from methanol,                                                                0-20                                                                              95    75                                                +7% HIS--OME/triethylamine                                              8     Rapid small evap. from methanol,                                                                0-20                                                                              92    80                                                +50% water                                                              9     Rapid small evap. from methanol,                                                                0-20                                                                               --98  --88                                             +5% filtrate residue                                                    10    Rapid small evap. from methanol,                                                                0-20                                                                              16    31                                                +10% dimethyl sulfoxide                                                 11    Rapid small evap. from methanol,                                                                0-20                                                                               --96  --87                                             +5% Z--D-PHE--HIS--OME                                                  12    Slow Evaporation from hot                                                                       70-90                                                                             67    63                                                methanol/water                                                          13    Large run similar to 9 (15 g)                                                                       88    75                                          14    Large run similar to 9 (15 g)                                                                       75    47                                          15    Medium run similar to 9 (7 g in 2 Hr)                                                                --98  --86                                       __________________________________________________________________________     .sup.(a) Cyanohydrination of 3phenoxybenzaldehyde with HCN to give            (S)--alphacyano-3-phenoxybenzyl alcohol.                                      .sup.(b) Small means 0.2 g of catalyst in 25 ml of solvent.              

EMBODIMENT 3

Solvent precipitation is another way of activating thecyclo(D-phenylalanyl-D-histidine)dipeptide, and Table 4 summarizes someresults using this approach. In all but one example shown, dimethylsulfoxide (DMSO) was used to dissolve the catalyst as a 5% solution, andthe dipeptide was precipitated by pouring this solution into awell-stirred vessel of second solvent, under a variety of conditions. Inmost cases, the precipitated catalyst formed a voluminous gel which wasrinsed with the second solvent to remove dimethyl sulfoxide and blowndry. In Experiments 5-14 urea (5% basis catalyst) was added to the DMSOsolution to aid in preventing crystallization of the dipeptide. In anycase, from the results shown, it appears that (a) of the fiveprecipitating solvents tested, dichloromethane and toluene appeared tobe best; (b) high temperature (80° C.) gave better results than lowertemperature (25° C.); (c) high dilution gave a better result than lowerdilution (compare Experiments 5 and 6); and (d) the catalystprecipitated from liquid ammonia solution (Experiment 4) was moderatelyactive (82% conversion in 3 hours) and quite selective (84% EE, evenafter 22 hours of contact with the catalyst). Unlike all of the othersthis product was a dense solid that was easy to filter and wash. Anumber of solvents for cyclo(PHE-HIS) shown in Table 1 can be used inthis approach, namely, DMSO, acetic acid, formamide,1-methyl-2-pyrrolidinone, dimethylformamide, N-methylformamide, liquidammonia, and the like.

                                      TABLE 4                                     __________________________________________________________________________    ACTIVATION OF CYCLO(D-PHENYLALANYL-D-HISTIDINE)                               BY SOLVENT PRECIPITATION                                                                                Cyanohydrination.sup.(d)                                                      Conversion                                                                          Enantiomeric                                  Experiment                                                                          Method of Precipitation                                                                           %/3 Hr                                                                              Excess, %                                     __________________________________________________________________________    1     From dimethyl sulfoxide (5%) into                                                                 65    41                                                  diethyl ether                                                           2     From dimethyl sulfoxide (5%) into                                                                 97    72                                                  toluene, 80° C.                                                  3     From dimethyl sulfoxide (5%) into                                                                 74    37                                                  toluene 25° C., large scale                                      4     From liquid NH.sub.3 (2%) into diethyl                                                            82      84.sup.(b)                                        ether, -40° C.                                                   5     From dimethyl sulfoxide.sup.(a) into 20 V                                                         42    31                                                  toluene, 25° C.                                                  6     From dimethyl sulfoxide into 5 V                                                                   4    10                                                  toluene, 25° C.                                                  7     From dimethyl sulfoxide into 20 V                                                                 85    57                                                  toluene, 80° C.                                                  8     From dimethyl sulfoxide into 20 V                                                                 77      37.sup.(e)                                        acetonitrile, 80° C./25° C.                               9     From dimethyl sulfoxide into 20 V                                                                  2      18.sup.(f)                                        acetonitrile, 25° C.                                             10    From dimethyl sulfoxide into 20 V                                                                  2      19.sup.(g)                                        tetrahydrofuran, 25° C.                                          11    From dimethyl sulfoxide into 20 V                                                                  2      0.sup.(c)                                         diethyl ether, 25° C.                                            12    From dimethyl sulfoxide into 20 V                                                                 77    49                                                  dichloromethane                                                         13    From dimethyl sulfoxide into 20 V                                                                 77    60                                                  tetrahydrofuran + 1% v/v H.sub.2 O, 25° C.                       14    Experiment 13 and vacuum oven dried                                                               89      50.sup.(h)                                  __________________________________________________________________________     .sup.(a) Catalyst 5% w/v in dimethyl sulfoxide, urea 5% basis catalyst.       .sup.(b) After 22 hours at 95% conversion.                                    .sup.(c) After 71 hours the enantiomeric excess was 24% at a conversion o     97%.                                                                          .sup.(d) Cyanohydrination of 3phenoxybenzaldehyde with HCN to give            (S)--alphacyano-3-phenoxybenzyl alcohol.                                      .sup.(e) At 92% conversion.                                                   .sup.(f) At 44% conversion.                                                   .sup.(g) At 49% conversion.                                                   .sup.(h) After 4 hours.                                                  

EMBODIMENT 4

Another method tested for activating the catalyst is freeze drying. Thisapproach requires a solvent for the dipeptide that freezes at aconvenient temperature and is volatile enough to be sublimed at belowthat temperature and at a practical pressure (vacuum). Of the solventstested, only water and acetic acid meet these requirements. The resultsof some of these tests are summarized in Table 5. Freeze drying of a0.1%w solution of the dipeptide in water gave an excellent product(Experiment 5). An attempt to freeze dry a solution in dimethylsulfoxide failed because the solvent was too high boiling to be sublimedat about 0° C. and 170 microns pressure. On the other hand, solutions inglacial acetic acid were readily freeze dried. The product from thisfreeze drying contains one mole of acetic acid per mole of catalyst. Inspite of this, the product was surprisingly active and selective(Experiment 2). This acid is relatively loosely held by the catalyst,and it was volatilized away in a sweep of air, on the one hand(Experiment 3), or neutralized by triethylamine treatment, on the other(Experiment 4). In both cases the products had about the sameactivity/selectivity: 93%/72%.

                                      TABLE 5                                     __________________________________________________________________________    ACTIVATION OF CYCLO(D-PHENYLALANYL-D-HISTIDINE)                               BY FREEZE DRYING                                                                                        Cyanohydrination.sup. (c)                                                     Conversion                                                                          Enantiomeric                                  Experiment                                                                          Solvent/Work Up     %/3 Hr                                                                              Excess, %.sup.(b)                             __________________________________________________________________________    1     From 2% solution in dimethyl sulfoxide                                                            --    --                                            2     From 1.9% solution in acetic acid                                                                 74    56 (6.5)                                      3     Product from experiment 2 air swept                                                               93    73 (5)                                              2 days                                                                  4     Product from Experiment 2 treated with                                                            93    72 (6.3)                                            triethylamine in diethyl ether                                          5     From 0.1% solution in water                                                                       98    85 (2.5)                                      __________________________________________________________________________     .sup.(a) Solution frozen at -40° C.; solvent sublimed at 0.1 Torr.     .sup.(b) Numbers in parentheses indicate time, in hours.                      .sup.(c) Cyanohydrination of 3phenoxybenzaldehyde with HCN to give            (S)--alphacyano-3-phenoxybenzyl alcohol.                                 

What is claimed is:
 1. A method for the cyanohydrination of an aldehydewith high enantiomeric selectivity wherein an aldehyde of the formula IV##STR6## wherein each A is independently a hydrogen atom, a halogen atomhaving an atomic number of from 9 to 35, inclusive, or an alkyl, alkenylor alkoxy group containing 1 to 6 carbon atoms, each optionallysubstituted by one or more halogen atoms having an atomic number of from9 to 35, inclusive; B is a group ##STR7## in which Y is 0; CH₂ ; C(O); mis 0 or 1 and D and E each independently is a hydrogen atom, a halogenatom having an atomic number of from 9 to 35, inclusive, or an alkyl,alkenyl or alkoxy group containing 1 to 6 carbon atoms, each optionallysubstituted by one or more halogen atoms having an atomic number of from9 to 35, inclusive, is cyanohydrinated in the presence of acyclo(D-phenylalanyl-D-histidine)dipeptide catalyst having 45% or moreof a non-crystalline or amorphous component of the dipeptide.
 2. Amethod according to claim 1 wherein 45% or more of the catalyst has anamorphous or non-crystalline component.
 3. A method according to claim 2wherein 65% or more of the catalyst has an amorphous or non-crystallinecomponent.
 4. A method according to claim 1 wherein a solidcyclo(D-phenylalanyl-D-histidine)dipeptide catalyst having asubstantially non-crystalline or amorphous component thereof, isprepared or activated by a method which is selected from (a) rapidevaporation of a solution of the catalyst, optionally in the presence ofimpurities or crystallinity inhibitors; (b) rapid precipitation of thecatalyst from a solution by dilution in a poor solvent; (c) freezedrying of a solution of the catalyst; (d) rapid cooling of the meltedcatalyst optionally in the presence of impurities or crystallinityinhibitors; or (e) use of crystallinity inhibitors duringsolidification.
 5. A method according to claim 4 wherein the method is(a) rapid evaporation of a solution of the catalyst.
 6. A methodaccording to claim 5 wherein the rapid evaporation is by spray drying.7. A method according to claim 4 wherein the method is (c) freezedrying.
 8. A method according to claim 1 wherein the aldehyde is3-phenoxybenzaldehyde.
 9. A process according to claim 1 wherein thedipeptide catalyst has 65% or more of a non-cyrstalline or amorphouscomponent of the dipeptide.